Human cancer results from the accumulation of independent genetic alterations which effect the transcriptional programs normally responsible for controlling cell growth and survival. Cancers within a single clinical category may exhibit seemingly disparate genetic defects that are, however, part of a common signal transduction pathway. The discovery of the wnt signalling pathway (summarised in FIG. 1) and the structure/function analysis of its distinct molecular components has provided an outstanding example for the identification of common denominators in oncogenesis (Polakis (2000) Genes & Development 14:1837–1851; Peifer and Polakis (2000) Science 287: 1606–1609).
Wnt signalling is initiated by members of the family of secreted wnt glycoproteins which bind to one or several of their specific cell surface receptors, designated frizzled. This family of seven-path-transmembrane receptors activate the dishevelled protein upon binding of their respective ligand. Associated with axin, dishevelled prevents glycogen synthase kinase-3β from phosphorylating critical substrates such as β-catenin. Other substrates include the negative regulators axin itself and APC. Unphosphorylated β-catenin escapes degradation via the ubiquitin pathway and translocates to the nucleus where it associates with transcription factors such as T-cell factor (TCF) and leucocyte enhancer factor (LEF). In mammals, the number of identified target genes transcriptionally regulated by way of wnt signalling is still limited but includes c-myc, cyclin D1, c-jun, matrix metalloproteinases and CD44.
There have been numerous reports on transcipional overexpression, and sometimes underexpression, of wnt genes in human cancers but mRNA expression levels are merely correlative. More compelling evidence for the involvement of wnt-mediated signals in neoplastic transformation stems from mutational analysis of regulatory genes operational in wnt signal transduction. For example, certain mutations in β-catenin render this protein refractory to inhibition by APC and thus prevent its degradation. In consequence, constituitive activation of β-catenin/TCF regulated gene transcription occurs. Similarly, mutational changes in APC and axin can disrupt the normal regulation of β-catenin and have been associated with various forms of tumours. Thus, characterizing wnt molecules, their signal transduction pathway and their biological effects will further aid the interpretation of direct and epigenetic evidence implicating wnts in oncogenesis including the generation of colorectal carcinoma, familial adenomatous polyposis, sporadic desmoid (i.e. aggressive fibromatosis), gastric cancer, hepatoblastoma, Wilm's tumor, melanoma, pancreatic tumors, anaplastic thyroid tumors, medulloblastoma, endometrial ovarian cancer, prostate cancer, and acute lymphoblastic leukemia.